Despite accumulating evidence suggesting a positive correlation between leptin levels, obesity, post-menopause and breast cancer incidence, our current knowledge on the mechanisms involved in these relationships is still incomplete. Our preliminary data show that specific leptin-induced signaling pathways are involved in the increased levels of factors related to angiogenesis and mitosis in syngeneic immuno-competent mouse models of mammary tumors (MT). The inhibition of leptin signaling in vitro and in vivo by our innovative leptin peptide receptor antagonists (LPrA) significantly reduced establishment and growth of MT and simultaneously decreased the levels of VEGF/VEGFR2. Specific cross-talk between leptin and IL-1 signaling found in endometrial and mammary cancer cells could be involved in their pro-angiogenic and anti-apoptotic effects. It is hypothesized that the leptin-induced effects on mammary cancer could occur upon leptin signaling the activation of Akt1/NFkB and an increased expression of VEGF/VEGFR2 and bcl-2, which may be linked to, or regulated, in part by IL-1 signaling. To test this hypothesis four models will be used in vitro and in vivo: (1) mouse mammary cancer cells implanted in syngeneic immuno-competent mice; (2) human breast cancer cells (responsive and irresponsive to estradiol) implanted in immuno-compromised mice; (3) human mammary epithelial cells treated with a carcinogenic agent (DMBA); (4) DMBA-MT induced in rats. The impact of leptin levels in establishment/ progression of MT in these rodent models will carefully be examined. To determine the effects of specific leptin-induced signaling pathways, kinase inhibitors, siRNAs, PEGylated-LPrAs (half-lives, 55h) will be used. Luciferase-VEGF promoter (mouse and human) and several transcription factor-reporters will be used to investigate leptin's targets in mouse and human mammary cancer cells. IL-1Ra inhibition of IL-1 signaling will serve to determine the impact of leptin/IL-1 signaling crosstalk on MT. This research would expand our limited knowledge on leptin/IL-1 signaling roles in MT and could generate essential data for new therapeutic strategies to target breast cancer, particularly for post-menopausal and obese women. Inhibition of leptin signaling in such instances might serve as a preventative or adjuvant measure.